The clostridial neurotoxins (CNTs), which include seven botulinum neurotoxin (BoNT) serotypes (A-G) and tetanus neurotoxin (TeNT), have been integral for studying neuroexocytosis. Intoxication by BoNTs causes flaccid paralysis whereas TeNT causes rigid paralysis. Because of these symptoms, Justinus Kerner envisioned the therapeutic potential of the BoNTs in the 1800s. Finally in 1989, BoNT/A (Botox®, Allergan Inc) and in 2000, BoNT/B (Myobloc™, Elan Pharmaceuticals Inc) were approved for treatment of human patients with facial nerve disorders and cervical dystonia, respectively.
Currently, most, if not all, therapeutic applications of the BoNTs involve the inhibition of neurotransmitter release from neurons. The targets for these toxins are neuronal SNARE proteins. SNAREs, which include syntaxin and SNAP-25 on the target membrane and synaptobrevin on vesicles, form the core of a conserved membrane fusion machine that mediates neuronal exocytosis. However, it is well established that SNARE proteins are ubiquitously expressed and are important for secretion in many other cell types, which include goblet cells in the lung and immune cells including eosinophils, neutrophils, macrophages, and mast cells. Inhibition of secretion from these cells, using CNTs, could revolutionize treatment options for cystic fibrosis (goblet cells), allergy (mast cells), and chronic inflammation (macrophages). However, the lack of toxin receptors naturally protects nonneuronal cells from the CNTs. Thus, the full therapeutic potential of these toxins has not been fulfilled due to their inability to target cells other than neurons.